SUMMARY Staphylococcus aureus is a major human pathogen of the respiratory tract and influenza co-infection is a major predisposing factor for subsequent infection. Increasing antibiotic resistance is a major concern and in the absence of a protective vaccine understanding the bacterial and host processes in infection will identify new treatment targets. The host inflammatory processes involved in S. aureus infection of the lung are not well understood, but we have identified the type III interferon pathway to be activated upon S. aureus infection. Type III interferon signaling contributes to the ability of S. aureus to colonize the nasopharynx as well as in the lung during acute pneumonia where they contribute to excessive immunopathology. This application will delineate the multiple mechanisms behind type III interferons contributing to S. aureus-induced disease. In Aim 1 we will investigate the influence of type III IFNs on neutrophil function and signaling and in Aim 2 we will examine their ability to influence the inflammasome. In Aim 3 we will determine how conserved activation of this pathway is across a variety of clinical specimens and identify the major cell types producing type III IFN. We will also examine the utility of IFN antibody neutralization in clearing infection under normal conditions and influenza co-infection, and in concert with current antimicrobials. We will utilize our recently developed humanized model of infection to confirm our observations in an improved model of infection. At the conclusion of these studies, we will have expanded our knowledge on how type III IFNs contribute to the pathogenesis of S. aureus pneumonia, and will have identified targetable mechanisms for therapeutic amelioration of host immunopathology due to IFN production.